Dr. Johansen was recently promoted to Professor of Medicine at the University of California, San Francisco (UCSF) with a long history of patient-oriented research (POR) focused on elucidating the degree of physical dysfunction among patients with chronic kidney disease, examining potential mechanisms for this dysfunction, and testing strategies to improve functioning in this population. Her overall career goals are to expand this line of research, becoming an internationally recognized investigator in this arena, and to increase her mentoring of junior investigators interested in POR. UCSF is a rich environment for training in POR, including an NIH-funded Clinical and Translational Sciences Institute (CTSI) offering a variety of opportunities, such as a K30-supported didactic training program in clinical research, a K12 (KL2) program, a Mentor Development program, which Dr. Johansen recently completed, as well as a Nephrology T32 that supports nephrology trainees in the pursuit of POR. This award would allow Dr. Johansen to reduce her clinical time in order to increase her POR and mentoring activities. The specific research to be supported under this award is an exploration of the prevalence and significance of frailty among patients new to dialysis. Frailty is a multidimensional construct reflecting a decline in health and functioning, initially observed in the elderly, that ultimately results in increased risk of disability, hospitalization, institutionalization, and death. We examined frailty in the USRDS Dialysis Morbidity and Mortality Study (DMMS) Wave 2 cohort and found that an extremely high proportion of incident ESRD patients, including many who were not elderly, met the criteria for frailty and that frailty was associated with greater risk of subsequent hospitalization and death. We recently completed data collection for a new USRDS special study, the Comprehensive Dialysis Study (CDS), in which 1,646 incident dialysis patients completed a questionnaire that asked about physical activity and functioning and health-related quality of life, providing the data needed for us to define a frailty phenotype based on low physical activity, poor physical functioning, and fatigue/exhaustion. We now propose to extend the investigation of frailty in ESRD by first determining the prevalence of frailty in this more modern dialysis cohort, then by capitalizing on the richness of the CDS data to delve deeper into the factors associated with frailty in this population and the relationship between frailty and ESRD process-related events and outcomes. We hypothesize that frailty is prevalent in this cohort and that frailty is independently associated with hospitalization and mortality as well as with ESRD-related outcomes such as type of vascular access and receipt of a transplanted kidney. Finally, we hypothesize that frailty is associated with depressed mood, post-dialysis fatigue, and sleep disturbance, all of which negatively affect quality of life in this population. It is hoped that these analyses will lead to better discrimination of dialysis patients at risk of adverse outcomes. Two new projects have been added to the revised application to address two of the components of the frailty phenotype: muscle wasting/weakness and physical inactivity. The first will extend Dr. Johansen's recent work evaluating the effects of oxidative stress on muscle fatigue to determine whether markers of oxidative stress are also associated with expression of proteins involved in the ubiquitin proteasome system, the major pathway of muscle catabolism. In addition, the muscle samples collected as part of Dr. Johansen's R21 project will also allow a preliminary assessment of whether short-term treatment with N-acetylcysteine, an anti-oxidant, is associated with reduced expression of catabolic proteins. In the second new project, Dr. Johansen will extend her previous work measuring physical activity in patients with ESRD to use pedometers as both an assessment tool and as a motivational tool in an intervention designed to increase physical activity in this population. PUBLIC HEALTH RELEVANCE: Because of the increasing number of new cases of ESRD in the US and the associated patient morbidity and costs, chronic kidney disease was designated as a focus area of Healthy People 2010, with the explicit goal to "reduce new cases of chronic kidney disease and its complications, disability, death, and economic costs." This project aims to investigate frailty, a major complication of ESRD, to determine the extent to which it increases the risk of death and hospitalization (a major contributor to the cost of ESRD). This application will also investigate oxidative stress as a potential contributor to frailty and the potential of a pedometer-based intervention to increase physical activity and improve physical performance and endothelial function. Results of this work may lead to further investigation of strategies to reduce frailty and thus increase quality of life and possibly reduce mortality or hospitalization in this population.